Human epidermal growth factor receptor-3 expression is regulated at transcriptional level in breast cancer settings by junctional adhesion molecule-a via a pathway involving beta-catenin and foxa1
(2021) In Cancers 13(4).- Abstract
The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between... (More)
The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.
(Less)
- author
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Anti-HER2 therapies, Breast cancer, Drug resistance, FOXA1, HER2, HER2-targeted therapies, HER3, JAM-A, Tight junction, Transcription factor, β-catenin
- in
- Cancers
- volume
- 13
- issue
- 4
- article number
- 871
- pages
- 25 pages
- publisher
- MDPI AG
- external identifiers
-
- scopus:85100940683
- pmid:33669586
- ISSN
- 2072-6694
- DOI
- 10.3390/cancers13040871
- language
- English
- LU publication?
- yes
- id
- 29b63776-75b3-4142-bc24-f80d87a3e220
- date added to LUP
- 2021-03-02 07:45:00
- date last changed
- 2024-04-18 02:32:28
@article{29b63776-75b3-4142-bc24-f80d87a3e220, abstract = {{<p>The success of breast cancer therapies targeting the human epidermal growth factor receptor-2 (HER2) is limited by the development of drug resistance by mechanisms including upregulation of HER3. Having reported that HER2 expression and resistance to HER2-targeted therapies can be regulated by Junctional Adhesion Molecule-A (JAM-A), this study investigated if JAM-A regulates HER3 expression. Expressional alteration of JAM-A in breast cancer cells was used to test expressional effects on HER3 and its effectors, alongside associated functional behaviors, in vitro and semi-in vivo. HER3 transcription factors were identified and tested for regulation by JAM-A. Finally a patient tissue microarray was used to interrogate connections between putative pathway components connecting JAM-A and HER3. This study reveals for the first time that HER3 and its effectors are regulated at gene/protein expression level by JAM-A in breast cancer cell lines; with functional consequences in in vitro and semi-in vivo models. In bioinformatic, cellular and patient tissue models, this was associated with regulation of the HER3 transcription factor FOXA1 by JAM-A via a pathway involving β-catenin. Our data suggest a novel model whereby JAM-A expression regulates β-catenin localization, in turn regulating FOXA1 expression, which could drive HER3 gene transcription. JAM-A merits investigation as a novel target to prevent upregulation of HER3 during the development of resistance to HER2-targeted therapies, or to reduce HER3-dependent tumorigenic signaling.</p>}}, author = {{Cruz, Rodrigo G.B. and Madden, Stephen F. and Richards, Cathy E. and Vellanki, Sri Harikrishna and Jahns, Hanne and Hudson, Lance and Fay, Joanna and O’farrell, Naoimh and Sheehan, Katherine and Jirström, Karin and Brennan, Kieran and Hopkins, Ann M.}}, issn = {{2072-6694}}, keywords = {{Anti-HER2 therapies; Breast cancer; Drug resistance; FOXA1; HER2; HER2-targeted therapies; HER3; JAM-A; Tight junction; Transcription factor; β-catenin}}, language = {{eng}}, number = {{4}}, publisher = {{MDPI AG}}, series = {{Cancers}}, title = {{Human epidermal growth factor receptor-3 expression is regulated at transcriptional level in breast cancer settings by junctional adhesion molecule-a via a pathway involving beta-catenin and foxa1}}, url = {{http://dx.doi.org/10.3390/cancers13040871}}, doi = {{10.3390/cancers13040871}}, volume = {{13}}, year = {{2021}}, }